Transcript Menstrual cycle suppression; an endocrine treatment Leslie Miller, M.D.

Menstrual cycle suppression;
an endocrine treatment
Leslie Miller, M.D.
Associate Professor OBGYN University of Washington
[email protected]
www.noperiod.com
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Is it more “natural” to have periods?
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100 years ago, menarche later
More gestations and lactation years
historically women 50 to 150 cycles
modern lifestyle up to 450 cycles
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RV Short. The evolution of human reproduction. Proc Royal Soc
London 1976; 195:3-24.
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“Excessive menstruation is an
iatrogenic disorder of communities
practicing any form of
contraception.”
RV Short. Why menstruate? Healthright 1985;4:9-12
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Is Menstruation Necessary?
• for successful human pregnancy
• to prepare for implantation
• NOT for contraception
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Hormones control bleeding
• If progestin dose high enough then ovarian
suppression, atrophy=amenorrhea
• Lower progestin dose=irregular bleeding
• Progestin thins endometrium
• Estrogen drives proliferation of lining
• Estrogen added to produce cyclic bleeds
• Cyclic withdrawal= regular bleeding
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An extended cycle is still a cycle
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90 women randomized to 28 vs 49 day
Monophasic 30 mcg EE2/300 NG
12 study cycles
Bleeding less but...
Spotting days similar even at end of year
Miller L, Notter K. Menstrual reduction with extended use of combination oral
contraceptive pills: randomized controlled trial. Obstet Gynecol 2001;98:7718.
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Why every “season”?
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30 mcg EE2/ 150 mcg Lng
84 days active, 7 spacers or 84-day cycle
456 women
40.6% dropped (35 quit because of bleeding)
4th pill pack (end of year) still 58.5%
BTB/spotting and half reported more than 4 days
Anderson FD, Hait H, the Seasonale 301 Study Group. A multicenter, randomized
study of an extended cycle oral contraceptive. Contraception 2003;68:89-96.
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Trying not to cycle
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30 EE/ 150 LNG 84-days or 91-day cycle
New patent “Seasonique”
Added 10 mcg of EE to the 7 spacer pills
1006 enrolled…50.3% quit early
Unscheduled bleed/spot 11 to 4 days/ cycle
Too much estrogen, LNG withdrawal= bleed
Anderson etal. Safety and efficacy of an extended regimen oral
contraceptive utilizing low dose ethinyl estradiol. Contraception
2006;73:229-234.
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Cycles= bleeding
• To induce bleeding withdrawal of hormones
• subsequent reintroduction of these hormones to
suppress the ovary and regenerate blood lining.
• Takes set time to bleed and then stop bleeding
• Likely it requires a higher dose to come back
without irregular bleeding after 7 days off.
• Likely there will not be a “perfect” withdrawal
bleed of 2 days every few months.
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Cycles= ovarian follicular activity
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36 women took 1 of 3 OC brands for 3 mos
47% developed a dominant follicle
86% of this occurred during pill free week
Associated with estradiol elevation
But no ovulation (compliant use)
Baerwald AR etal. Ovarian follicular development is initiated during the
pill free interval of OC use. Contraception 2004;70:371-7.
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Reducing the pill free interval
• Pill free interval of 4 days
• 20 mcg 24-day products, more ovarian
suppression, but more irregular bleeding
unless weak progestin…but why cycle?
Sullivan H, Furniss H, Spona J, Elstein M. Effect of 21-day and 24-day oral
contraceptive regimens contraining gestodene (60 mcg) and ethinyl estradiol
(15 mcg) on ovarian activity. Fertil steril 1999;72:115-20. Fruzzetti F et al. A
12 month clinical investigation with a 24 day regimen containing 15 mcg EE2
plus 60 mcg gestodene with respect to hemostasis and cycle control.
Contraception 2001;63:303-7.Contraception 2006;73:30-33.
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Beware of PMS advertising
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450 women with PMDD
Placebo vs OC (24-day 20 EE/3 DSP)
3 treatment cycles
50% reduction of daily Sx scores in 48% of
women on OC vs 36% response with
placebo = FDA indication
• No comparison to other OC or continuous
Yonkers etal. Efficacy of a new low dose OC with drospirenone in premenstrual
dysphoric disorder. Obstet Gynecol 2005;106:492-501. Barbosa etal. Minesse
cycle control. Contraception 2006;73:30-33.
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Continuous OC suppresses ovary
• Open label comparison of 4 OC doses (all
30-35mcg of ethinyl estradiol with use
continuous for 3 months vs cyclic
• Fewer follicles > 4 mm with daily use
• No follicle ≥ 10 mm with daily use
Birtch etal. Ovarian follicular dynamics during conventional vs
continuous OC use. Contraception 2006;73:235-43.
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Continuous HRT
• Originally cyclic prescribed for HRT too
• Continuous HRT biopsy=less proliferative
compared to cyclic progestin=safer
• By 6 months 70-80% amenorrhea
Sturdee DW, et al. The endometrial response to sequential and continuous
combined oestrogen progestogen replacement therapy. British J Obstet and
Gyn 2000;107:1392-1400. Raudaskoski et al. Intrauterine 10 mcg and 20 mcg
IUS in postmenopausal women on ERT compared to cyclic oral provera.
BJOG 2002;109:136-44.
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Continuous OC for endometriosis
• Enovid used in 1959 to induce “pseudopregnancy” up to 3 yrs, Robert Kistner
• Continuous 20 mcg EE2/DSG effective for
up to 2 years in endometriosis patients
Vercellini P, etal. Continuous use of an oral contraceptive for endometriosisassociated recurrent dysmenorrhea that does not respond to a cyclic pill
regimen. Fert Steril 2003;80:560-3.
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Eliminate the pill free interval
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RCT daily vs cyclic vaginal 50mcg OCP
70% amenorrhea by 3 months, 90% by 1 yr
No pregnancies with daily OC use
4 pregnancies with cyclic use
Coutinho EM et al. Comparative study on intermittent versus continuous use
of a contraceptive pill administered by vaginal route. Contraception
1995;51:355-58.
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Continuous OCP RCT
• 79 randomized to either daily 20 mcg
EE2/100 mcg Lng or 28 day cycle
• For one year
• 32 continuous and 28 cyclic completed
• Discontinuation rates similar (p=0.6)
Miller L, Hughes JP. Continuous combination oral contraceptive pills to eliminate
withdrawal bleeding: a randomized trial. Obstet Gynecol 2003;101:653-61.
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Percent not bleeding
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To get Amenorrhea, takes time…
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Overall spotting days no difference
But days 1-21 spotting until cycle 6
22% with a bleeding episode >10 days
16% amenorrhea cycles 1-3
72% amenorrhea cycles 10-12
Miller L, Hughes JP. Continuous combination oral contraceptive pills to eliminate
withdrawal bleeding: a randomized trial. Obstet Gynecol 2003;101:653-61.
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What is the best daily “recipe”?
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monophasic formulation
lower estrogen dose=less proliferation
daily 20 mcg EE2 < cyclic 30 mcg EE2
Lng and NETA, old favorites, safer, generic
What we really need are pills in bottle
Could be like thyroid medication
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Progestin type may matter
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139 women randomized
All cyclic OC switchers
4 doses (20 vs 30 EE/LNG vs NETA)
6 months; 38% to 72% completed study
Edelman etal. Continuous oral contraceptives. Are bleeding patterns
dependent on the hormones given? Obstet Gynecol 2006;107:657-65.
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↑Amenorrhea with ↓EE and NETA
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Desogestrel=more bleeding
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177 OC switchers after 2 run-in cycles
126 days of 30 EE/3 DSG (80.8% completed)
Median day to 1st bleed day=99 (51, 127)
10.7% quit for unacceptable bleeding
Median bleed/spot days 17.0 (5.0, 32.0)
45.2% bled for ≥ 20 days
Foidart etal. The use of an OC containing ethinyl estradiol and
drospirenone in an extended regimen over 126 days. Contraception
2006;73:34-40.
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Cardiovascular risk increased with
“third generation” progestins
• WHO study on inflammatory markers
• Higher c-reactive protein, fibrinogen, and
blood viscosity with DSG or gestodene
• Doubles risk and worse for smokers
Doring A, etal. Third generation oral contraceptive use and
cardiovascular risk factors. Atherosclerosis 2004;172:281-6.
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If a progestin is not “androgenic”
then it can increase estrogen effects
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Lng vs Desogestrel 30 mcg EE COC
Significant differences in SHBG
↑60% with Lng and ↑280% with DSG
Associated with prothrombotic changes too
• Drospirenone…could have risks too
Van Rooijen M, Silvera A, Hamsten A, Bremme K. Sex hormone binding
globulin. A surrogate marker for the prothrombotic effects of combined
oral contraceptives. Am J Obstet Gynecol 2004;190:332-7.
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Estrogen increases SHBG...
Perhaps not great for the libido
• “chronic SHBG elevation led to low levels of
bioavailable testosterone/androgen insufficiency”
• 62 women on OC, 39 stopped OC, 23 never OC
• SHBG levels 4 fold higher with OC
• Even 6 months off OC better but still elevated
Panzer etal. Impact of OC on SHBG and androgen levels. A retrospective
study in women with sexual dysfunction. J Sex Med 2006;3:104-113.
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12 weeks (84 days) of patch use
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155 women randomized to extended
Compared to 80 women to 28-day cycle
only 12% reported amenorrhea over 84-days
Half did not bleed until after day 54
3x more breast tenderness/nausea if extend
Headache (18% if extend vs 3%) but extension
does decrease headaches in patch free week
Stewart etal. Extended use of transdermal norelgestromin/ethinyl
estradiol. Obstet Gynecol 2005;105:1389-96. Fertil Steril
2005;83:1875-77.
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Tmax versus AUC
• Pills…only a few
hours of elevated EE
• Pregnancy is also a
time of continuous
estrogen exposure= ↑
thrombosis
Contraception 2005;72:168-74
Contraception 2006;73:223-8
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Comparison of 4 ring schedules
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429 women randomized, 67% finished year
28-day, 49-day, 91-day, 364-day
Longer cycles more unscheduled bleeding
20 women quit 364-day vs only 5 in 49-day
arm for unacceptable bleeding
Miller etal. Extended regimens of the contraceptive vaginal
ring. Obstet Gynecol 2005;106:473-82.
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What about Pregnancy?
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Many other methods change the period
Pregnancy tests cheap and easy to do
Daily pill use very unlikely to get pregnant
Needed pill free week and missed pills to ovulate
And the modern OCP is not a teratogen except
spironolactone is and perhaps drospirenone is
Letterie G, Chow G. Effect of missed pills on oral contraceptive pill effectiveness.
Obstet Gynecol 1992;79:979-82.Bracken MB. Oral contraception and congenital
malformations in offspring: a review and metaanalysis of the prospective studies.
Obstet Gynecol 1990;76:552-7.
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Return to fertility
• Reversible
• Little prospective data
• Could be a rebound
effect in FSH?
• Ovulate before bleed!
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Possible risk of higher EE2
with the loss of hormone free week
• No reversal of hepatic changes
• Dose accumulation
• 42 day cycles increased SHBG/HDL
• Lower EE2 prudent and ↓ side-effects?
McGurgan P, O’Donovan P, Duffy S, rogerson L. Should menstruation be optional
for women? Lancet 2000;355:1730. Oral contraceptive and hemostasis study
group. The effects of seven monophasic OC regimens on hemostatic variables.
Contraception 2003;67:173-185. Cachrimanidou AC et al. Hemostasis profile
and lipid metabolism with long interval use of desogestrel containing oral
contraceptive. Contraception 1994;50:153-65.
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Bone density
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Little natural estradiol production
Exogenous EE2 important
Proven no loss unlike DMPA
But will peak bone density be reached?
Cromer BA etal. A prospective comparison of bone density in adolescent girls
receiving DMPA, norplant, or OC. J Pediatr 1996;129:671-6. Berenson AB
etal. A prospective, controlled study of the effects of hormonal contraception
on bone mineral density. Obstet Gynecol 2001;98:576-82. Polatti F etal. Bone
Mass and longterm monophasic OC treatment in young women. Contraception
1995;51:221-4.
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Chemoprevention of cancer
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Ovulation suppression likely important
But also progestin induced apoptosis
Is it dose or regimen?
Could continuous OC also prevent breast cancer?
Schildkraut JM etal. Impact of progestin and estrogen potency in oral
contraceptives on ovarian cancer risk. J Natl Cancer Inst 2002;94:32-8. Pike
MC, Spicer DV. Hormonal contraception and chemoprevention of female
cancers. Endocrine Related Cancer 2000;7:73-83. Ursin G etal.
Mammographic density changes during the menstrual cycle. Cancer
epidemiology biomarkers and prevention 2001;10:141-2.
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Could anemia be protective?
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Hemochromatosis, Polycythemia vera ↑ males
↑ Thrombosis 
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↑ viscosity
Atherosclerosis↑ with ↑ ferritin
Could check ferritin and CBC
And donate blood
Kiechl S, Willeit J, Egger G, Poewe W, Oberhollenzer F, the Bruneck
Study Group. Body iron stores and the risk of carotid
atherosclerosis. Circulation 1997;96:3300-7. Sullivan JL. The iron
paradigm of ischemic heart disease. American Heart Journal
1989;117:1177-1188.
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Counseling Women
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Introduce the idea but don’t over sell it
She must want this
To expect irregular bleeding and spotting
Keep a menstrual diary
See regularly to help problem solve
Emphasize the other benefits
Ask about her partner’s concerns
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Irregular bleeding…expect it
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Withdraw first if history of irregular menses?
Atrophy after one cycle of progestin likely
Stop “to have a period” counter productive?
More estrogen = fuel on the fire?
6 months to suppress ovarian hormones?
Various things to try…vit C, NSAIDS, BID doses
A progestin switch can work, why? Time?
Remember to check HCG, US, even EMB…
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Change the paradigm
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Avoid brand names
Think “what hormones” “what dose”
Imagine like other endocrine conditions
Monitor response…adjust dose as needed to
treat “ovulation” and “menses”
• We don’t need new patents…
• Why not just 31 pills in a bottle?
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